PROJECT SUMMARY/ABSTRACT The Candidate: Dr. Rau is highly motivated and exceptionally qualified to pursue a career as an independent academic physician-scientist in the field of oncology. She is driven by an intense desire to improve the care of patients afflicted with hematologic malignancies, with the understanding that advances in care will arise only through deep investigation of the underlying mechanisms that drive these diseases. It has become increasingly clear that epigenetic dysregulation contributes substantially to the genesis of hematologic diseases, however the underlying mechanisms are poorly understood. Dr. Rau aims to establish an independent research program focused on understanding these epigenetic perturbations with the intention of ultimately impacting the way patients with hematologic malignancies are cared for. Research Career Development Plan: Dr. Rau will utilize an array of educational and research resources in the Texas Medical Center to strengthen her research career development. Within the Baylor College of Medicine (BCM) graduate programs in biomedical sciences, she will enroll in courses relevant to her research including translational cancer biology, bioinformatics, and computer aided discovery methods. Dr. Rau will continue her highly productive research training under the mentorship of Dr. Margaret Goodell, an internationally recognized stem cell biologist who is equally recognized for her mentoring skills. Dr. Rau's superb advisory committee will continue to guide her research and career development during formal meetings and one-on-one interactions. BCM and her department have invested in her career development by assuring 75% protected time for research regardless of receipt of this or other career development award. Research Project: DNMT3A mutations are common in acute myeloid leukemia (AML) and portend a poor prognosis. Dr. Rau observed that Dnmt3a?/? murine HSCs overexpress the histone 3, lysine 79 (H3K79) methyltransferase, Dot1l, leading to the hypothesis that DOT1L may play a central role in the pathogenesis of DNMT3A-mutant AML, which is supported by extensive preliminary data generated by Dr. Rau. Here, she will determine the precise role of H3K79me in Dnmt3a?/? HSCs by examining the impact of Dot1l-knockdown on DNA methylation, gene expression, and malignant transformation using murine models. She will also examine human AML cells for the interplay between H3K79me, DNA methylation and gene expression, and determine the mechanisms by which DOT1L inhibition exerts therapeutic efficacy in DNMT3A-mutant AML by mapping changes in H3K79me, DNA methylation and gene expression with DOT1L inhibitor treatment. This work willl greatly enhance the understanding of the pathogenesis of DNMT3A-mediated leukemia, and will provide critical information about the interations between DNA methylation and histone modifications in the pathogenesis of hematologic malignacies more broadly. Therefore, this project will serve as a strong foundation on which Dr. Rau will build her independent research career.